Patent GB-921943-A (GB)
Title: Anti-hypertensive compositions
IPC: A61K31/13
Filed: 1960-11-18
Abstract: The invention relates to amines of the formula:-<FORM:0921943/IV(a)/1> and acid addition salts thereof, wherein R1 is hydrogen, methyl, ethyl or propyl; R2 is alkyl or alkenyl of 1-7 carbon atoms the sum of the carbon atoms in R1 and R2 being greater than 1 and R1 and R2 together may be unsubstituted tetramethylene or tetramethylene group substituted by alkyl or alkenyl said group containing a maximum of 10 carbon atoms; R3 and R4 are alkyl groups of 1 to 4 carbon atoms the sum of the carbon atoms in R3 and R4 being less than 8 and R5 is an alkyl, alkenyl or alkynyl group of 2-4 carbon atoms, acetyl or an a -hydroxyethyl radical.  The secondary and tertiary amino acetylenes are prepared by heating the corresponding chloroacetylene or hydroxyacetylene with a primary or secondary amine.  The tertiary amino acetylenes can also be prepared by alkylation of the corresponding secondary amino acetylene.  The amino ethylenes and the saturated amines are prepared by catalytic hydrogenation of the corresponding amino acetylene or ethylene.  The secondary and tertiary amino ketones are produced by hydrating the corresponding amino acetylene e.g. with aqueous sulphuric acid and the hydroxy amines by reduction of the thus formed amino ketones with sodium borohydride or lithium aluminium hydride.  The secondary and tertiary amino acetylenes, ethylenes, alcohols and saturated amines may also be prepared by alkylation of the corresponding primary amine using an alkylating agent such as formaldehyde and formic acid, an alkyl halide, an alkyl p-toluene sulphonate, a dialkyl sulphate or an alkyl sulphonate. 3-isopropyl-4-methyl-1-pentyne-3-ol one of the hydroxy acetylenes referred to above is prepared by passing acetylene into liquid ammonia while adding sodium and then adding di-isopropyl ketone while still passing acetylene.  3-methyl-1-heptyn-3-ol; 3,4,4-trimethyl-1-pentyn-3-ol and 3,4-dimethyl-1-hexyn-3-ol are prepared in a similar manner.  3-chloro-3-methyl-1-butyne one of the chloro acetylenes referred to above is prepared by mixing calcium chloride, copper bronze powder and 3-methyl-1-butyne-3-ol together and then adding 12 N. HCl. 3-chloro-3-isopropyl-4-methyl-1-pentyne 3-chloro-3,4-dimethyl - 1 - hexyne; 3 - chloro-3,4-dimethyl-1-pentyne; 3 - chloro - 3 - methyl-1-heptyne; 3-chloro-3-methyl-1-hexyne; 3-chloro-3-ethyl-1-hexyne; and 3-chloro-3,4,4-trimethyl-1-pentyne are prepared in a similar manner. Specified amines and salts prepared:- 3-isopropyl-amino-3-methyl-1-butyne; 3 - t - butylamino-3-methyl-1-butyne; 3-isopropylamino-3-ethyl-1-pentyne; 3-isopropylamino-3-methyl-1-hexyne; 3 - allylamino - 3 - methyl-1-butyne; 3-t-butylamino-3-methyl-1-butene; 3-isopropylamino-3,4-dimethyl-1-pentene; 3-ethylamino-3-methyl-butane; 3-t-butylamino-3-methylbutane; 3-t-butylamino-3-methyl-2-pentanone 3-t-butylamino-3-methyl-2-butanone; 3-t-butylamino-3-ethyl-2-pentanone; 3-isopropylamino-3-ethyl-2-pentanol; 3 - t - butylamino-3-methyl-2-butanol and the hydrochlorides thereof; 3-t-butylamino-3-methyl-1-butyne; 3-isopropylamino-3-methyl - 1 - butyne-sulphate and 3-isopropylamino - 3 - methyl - 1 - butene succinate.  The amines and salts may be used in pharmaceutical compositions (see Group VI).ALSO:An anti-hypertensive composition for oral or parenteral administration comprises an hypotensive amine of formula <FORM:0921943/VI/1> wherein R1 is hydrogen, methyl, ethyl or propyl; R2 is an alkyl or alkenyl radical having from 1-7 carbon atoms, the sum of the carbon atoms in R1 and R2 being greater than 1, and R1 and R2 when taken together form an unsubstituted tetramethylene group or an alkyl or alkenyl substituted tetramethylene group having not more than 10 carbon atoms; R3 and R4 are alkyl groups having from 1 to 4 carbon atoms, the sum of the carbon atoms in R3 and R4 being less than 8; and R5 is an alkyl, alkenyl or alkynyl radical or 2-4 carbon atoms, the acetyl or a -hydroxy ethyl radical, or a non-toxic acid addition salt thereof dispered in a pharmaceutically acceptable extending medium except water or a common organic solvent alone.  Many amines are specified typical examples are 3 - t - butylamino - 3 - methyl - 1 - butyne, 3 - t - amylamino - 3 - ethyl - 2 - butanone, 3 - isopropylamino - 3 - ethyl - 1 - heptene benzoate, 3 - isopropylamino - 3 - ethyl - 2 - pentanol, 3-t - butylamino - 3 - methyl butane hydrochloride and 3 - pyrrolidino - 3 - ethyl - 1-pentyne.  Specified acids forming salts are hydrochloric, sulphuric, phosphoric hydrobromic, maleic, cinnamic, benzoic and tartaric acid. Specified pharmaceutical forms are tablets, capsules, elixirs, suspensions, ampoules, enteric-coated tablets, micro-encapsulations or adsorbates on ion exchange resins. Carriers are starch, gelatin capsules, milk sugar and magnesium stearate.  For preparation of the hypotensive amines of the invention see Group IV (b).